Devices and methods for enhanced denervation procedures

ABSTRACT

The present disclosure relates to methods, devices, kits and systems for enhancing the efficacy and longevity of denervation procedures.

PRIORITY

This application claims the benefit of priority under 35 U.S.C. § 119 toU.S. Provisional Application Ser. No. 62/258,986, filed Nov. 23, 2015,which is incorporated by reference in its entirety and for all purposes.

FIELD

The present disclosure relates to methods, devices, kits and systems forenhancing the efficacy and longevity of denervation procedures.

BACKGROUND

Existing technology used for denervation for chronic pain primarilyincludes radiofrequency ablation (RFA), which is commonly performed in amonopolar configuration where current is passed between a probe and aground pad. Unfortunately, nerve fibers regenerate over time, leading tothe need for repeated denervation procedures for the management of pain.

The present disclosure pertains to devices and methods for use ininhibiting nerve regeneration after the performance of denervationprocedures, including RFA denervation procedures, among others, for thetreatment of pain, as well as numerous other therapies as detailedbelow.

SUMMARY

In some aspects of the present disclosure, a method of treatment isprovided, which comprises (a) conducting a denervation procedure at atarget site in a subject, (b) introducing at least one agent thatinhibits or prevents nerve regeneration to the target site and (c)optionally introducing an anesthetic agent to the target site.

In some aspects of the present disclosure, a system is provided, whichcomprises (a) means for conducting a denervation procedure at a targetsite in a subject and (b) means for introducing at least one agent thatinhibits or prevents nerve regeneration to the target site and (c)optional means for introducing one or more anesthetic agents to thetarget site

In some embodiments, which may be used in conjunction with any of thepreceding aspects, the denervation procedure may be a radiofrequencyablation (RFA) procedure.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the at least one agent that inhibits orprevents nerve regeneration may be a chemical agent. In some instances,the chemical agent may be introduced to the target site as an injectablecomposition, which may be, for example, in the form of a solution, a gelor a dispersion of particles, among other possible forms. Alternativelyor in addition, the chemical agent may be introduced to the target siteas an encapsulated solid, liquid, gel or dispersion. Alternatively or inaddition, the chemical agent may be introduced to the target site byfilling a reservoir by injection in vivo, in which case the reservoirmay optionally comprise one or more surface electrodes. Alternatively orin addition, a device that contains the chemical agent may be clampedaround a severed nerve and wherein the device exposes the severed nerveto the chemical agent.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, a solid material may be provided at thetarget site. In some instances, the solid material may comprise animaging agent. Alternatively or in addition, the solid material maycomprise a chemical agent that inhibits or prevents nerve regeneration.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, a solid material may be formed at thetarget site.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, a solid material may be introduced to thetarget site. For example, the solid material may be a detachablematerial that may be positioned at a distal end of a medical device,which may be, for instance, an ablation device, among otherpossibilities.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, a solid material may be introduced to thetarget site in the form of a detachable sheath. In some instances, themedical device may comprise an ablation electrode and the detachablesheath may be disposed over the ablation electrode. Alternatively or inaddition, the medical device may comprise a lumen through which a vacuumsource applied to the detachable sheath. Alternatively or in addition,the detachable sheath may comprise an agent or device that causes anablated nerve to grow into the sheath.

In some aspects, the present disclosure provides a radiofrequencyablation device that comprises (a) a needle electrode configured toperform a radiofrequency ablation procedure and (b) a detachable sheathdisposed over the needle electrode.

In some embodiments, the sheath of the radiofrequency ablation devicemay be crumpled when detached from the needle electrode.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the sheath may comprise one or morechemical agents. The one or more chemical agents may be, for example,released from the sheath after detachment of the sheath within asubject. The one or more chemical agents may comprise, for example, anagent that inhibits or prevents nerve regeneration, an anesthetic agent,or a combination of both.

In some aspects, the present disclosure provides a device that may beconfigured to clamp around and sever a nerve fiber and release achemical agent that inhibits or prevents nerve regeneration in thepresence of the severed nerve fiber. The device may comprise, for,example, one or more blades configured to sever the nerve fiber.

In some aspects, the present disclosure provides a kit that comprises(a) an implantable reservoir and (b) a catheter, wherein the implantablereservoir is configured to inhibit or prevent nerve regeneration at atarget site in a patient.

In some embodiments, which may be used in conjunction with any of thepreceding aspects, the catheter may be configured to deliverradiofrequency ablation energy to the target site. In certain of theseembodiments, the implantable reservoir may comprise electrodes and thecatheter may be configured to deliver the radiofrequency ablation energyto the electrodes.

In some embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the reservoir may be configured torelease at least one agent that inhibits or prevents nerve regenerationat the target site. The at least one agent that inhibits or preventsnerve regeneration may be introduced, for example, in the form of asolution, a gel, a dispersion, or a solid material, among others.

In certain embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the implantable reservoir may comprise alumen that is configured to receive the at least one agent that inhibitsor prevents nerve regeneration, and the catheter may be configured tointroduce the at least one agent that inhibits or prevents nerveregeneration into the lumen at the target site. The implantablereservoir may be an inflatable implantable reservoir in certaininstances.

In certain embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the catheter may comprises a needleelectrode configured to perform a radiofrequency ablation procedure, andthe implantable reservoir may comprise a detachable sheath that isdisposed over the needle electrode. The detachable sheath may, forexample, become crumpled when detached from the needle electrode. Thedetachable sheath may, for example, release a chemical agent thatinhibits or prevents nerve regeneration after detachment of the sheathwithin a subject. The detachable sheath may, for example, comprise anagent that causes an ablated nerve to grow into the sheath. The cathetermay, in certain cases, comprise a lumen through which a vacuum source isapplied to the detachable sheath.

In certain embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the implantable reservoir may comprise adevice that is configured to clamp around and sever a nerve fiber andrelease at least one agent that inhibits or prevents nerve regenerationin the presence of the severed nerve fiber. In certain cases, the devicemay comprise one or more blades configured to sever the nerve fiber.

In certain embodiments, which may be used in conjunction with any of theabove aspects and embodiments, the kit may be configured to introduce ananesthetic agent to the target site.

Other aspects and embodiments, as well as various advantages of thepresent disclosure will become immediately apparent to those of ordinaryskill in the art upon review of the detailed description and claims tofollow

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are schematic side views illustrating a denervationprocedure in accordance with an embodiment of the present disclosure.

FIG. 2 is a schematic side view of an ablation device, in accordancewith an embodiment of the present disclosure.

FIG. 3A is a schematic side view of an ablation device, in accordancewith an embodiment of the present disclosure.

FIGS. 3B-3D are schematic side views of detachable sheaths, inaccordance with three embodiments of the present disclosure.

FIG. 4 is a schematic side view illustrating an ablation device beingused in conjunction with an ablation procedure, in accordance with anembodiment of the present disclosure.

FIG. 5 is a schematic side view of an ablation device, in accordancewith an embodiment of the present disclosure.

FIG. 6 is a schematic side view illustrating an ablation device beingused in conjunction with an ablation procedure, in accordance with anembodiment of the present disclosure.

DETAILED DESCRIPTION

The devices and methods of the present disclosure are useful in avariety of denervation treatments, including denervation therapy at ananatomical location for targeted relief of chronic pain (e.g. facetjoint, sacroiliac joint, knee, foot, and hip), as well as clinicaldenervation procedures for the treatment of hypertension, includingpulmonary arterial hypertension, asthma, chronic obstructive pulmonarydisease (COPD), diabetes, metabolic syndrome, heart failure,arrhythmias, chronic kidney disease, obstructive sleep apnea andoveractive bladder, among others, and may be used in conjunction withvarious denervation techniques, including denervation based onradiofrequency energy (including conventional monopolar RF, bipolar RF,multipolar RF), laser energy, ultrasound (e.g., high intensity focusedultrasound) and microwave energy sources, cryogenic denervationprocedures, and chemical denervation procedures, among others.

Thus, while the devices and methods of the present disclosure aretypically described herein in the context of RF ablation procedures, inmany cases, they are applicable to other ablation procedures as well.

In various embodiments, the present disclosure is directed to devicesand methods for inhibiting nerve regeneration following a denervationprocedure, which utilize chemical agents that inhibit or prevent nerveregrowth (also referred to as “agents that inhibit or prevent nerveregeneration” or simply “anti-regeneration agents”). These agentsinclude inorganic and organic chemical agents, including small moleculeorganic chemical agents, biochemical agents, which may be derived fromthe patient and/or from an external source such as an animal sourceand/or a synthetic biochemical source, and cell-based therapies.

Some specific examples of anti-regeneration agents that may be used inconjunction with the present disclosure include the following, amongothers: (a) capsaicin, resiniferatoxin and other capsaicinoids (see,e.g., J. Szolcsanyi et al., “Resiniferatoxin: an ultrapotent selectivemodulator of capsaicin-sensitive primary afferent neurons”, J PharmacolExp Ther. 1990 November; 255(2):923-8); (b) taxols including paclitaxeland docetaxel (i.e., at concentrations are sufficiently elevated to slowor cease nerve regeneration, as lower concentrations of paclitaxel mayfacilitate nerve regeneration; see, e.g., W. B. Derry, et al.,“Substoichiometric binding of taxol suppresses microtubule dynamics,”Biochemistry 1995 February 21;34(7):2203-11), botox, purine analogs(see, e.g., L A Greene et al., “Purine analogs inhibit nerve growthfactor-promoted neurite outgrowth by sympathetic and sensory neurons,”The Journal of Neuroscience, 1 May 1990, 10(5): 1479-1485); (c) organicsolvents (e.g., acetone, aniline, cyclohexane, ethylene glycol, ethanol,etc.); (d) vinca alkaloids including vincristine, vindesine andvinorelbine, and other anti-microtubule agents such as nocodazole andcolchicine; (e) platinum-based antineoplastic drugs (platins) such ascisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatinand triplatin; (f) ZnSO₄ (i.e., neurodegenerative factor); (g) latarcins(short linear antimicrobial and cytolytic peptides, which may be derivedfrom the venom of the spider Lachesana tarabaevi); (h) chondroitinsulfate proteoglycans (CSPGs) such as aggrecan (CSPG1), versican(CSPG2), neurocan (CSPG3), melanoma-associated chondroitin sulfateproteoglycan or NG2 (CSPG4), CSPGS, SMC3 (CSPG6), brevican (CSPG7), CD44(CSPG8) and phosphacan (see, e.g., Shen Y et al. “PTPsigma is a receptorfor chondroitin sulfate proteoglycan, an inhibitor of neuralregeneration”, Science, 2009 October 23; 326(5952):592-6); (i)myelin-associated glycoprotein (MAG); (j) oligodendrocytes; (k)oligodendrocyte-myelin glycoprotein; and (I) Reticulon-4, also known asNeurite outgrowth inhibitor or Nogo, which is a protein that in humansis encoded by the RTN4 gene (see, e.g., Lynda J.-S. Yang et al., “Axonregeneration inhibitors, Neurological Research, 1 Dec. 2008, Volume 30,Issue 10, pp. 1047-1052).

Further examples of anti-regeneration agents suitable for use in thepresent disclosure include agents that induce the formation of a glialscar which has been shown to inhibit nerve regeneration after spinalcord injury, which may be selected from the following, among others: (a)laminin, fibronectin, tenascin C, and proteoglycans, which have beenshown in inhibit axon regeneration (see, e.g., Stephen J. A. Davies etal., “Regeneration of adult axons in white matter tracts of the centralnervous system,” Nature 390, 680-683 (18 Dec. 1997); (b) reactiveastrocyte cells, which are the main cellular component of the glialscar, which form dense web of plasma membrane extensions and whichmodify extracellular matrix by secreting many molecules includinglaminin, fibronectin, tenascin C, and proteoglycans; (c) molecularmediators known to induce glial scar formation including transforminggrowth factor β (TGF β) such as TGFβ-1 and TGFβ-2, interleukins,cytokines such as interferon-γ (IFNγ), fibroblast growth factor 2(FGF2), and ciliary neurotrophic factor; (d) glycoproteins andproteoglycans that promote basal membrane growth (see, e.g., CC Stichelet al., “The CNS lesion scar: new vistas on an old regenerationbarrier”, Cell Tissue Res. (October 1998) 294 (1): 1-9); and (e)substances that deactivate Schwann cells.

Still other examples of anti-regeneration agents for use in the presentdisclosure include Semaphorin-3A protein (SEMA3A) (which may be used toinduce the collapse and paralysis of neuronal growth cones), calcium(which may lead to turning of nerve growth cones induced by localizedincreases in intracellular calcium ions), methylene blue, andradioactive particles.

As noted above, in certain cases, anti-regeneration agents may beobtained from the subject being treated. For example, a needle may beused for suctioning, cutting and aspirating nerve fibers. The aspiratemay then be processed to extract and concentrate anti-regenerationfactors present such as Nogo, chondroitin sulfate proteoglycans andother glycoproteins (e.g., in the form of a liquid extract, sheet,fiber, powder, etc.), which may be injected to the site of ablationpost-processing, for example, via member left in place at the targetsite (e.g., a hollow needle used for RFA, through which theanti-regeneration factors may be introduced, as discussed below).

Additionally, certain aspects of the invention will relieve the patientof pain in the short-term post-procedure timeframe where increased painover baseline may be experienced due to local tissue reaction to theablation procedure. Examples of suitable anesthetic agents for thispurpose include, for instance, bupivicaine, ropivicane, lidocaine, orthe like, which can be released to provide short-term local pain reliefpost-procedure around the treatment region.

The anesthetic agent may be released over a timeframe of 14 days orless, preferably 7 days or less. The anti-regeneration agent may bereleased over an appropriate timeframe, or at specific intervals intime, for the particular agent to effectively block nerve regenerationfrom occurring.

In various aspects, the devices and methods of the present disclosuremay achieve a longer-lasting denervation effect (i.e., significantlylonger than the current ˜9 months achieved with RFA) than that observedin the absence of such devices and methods.

Turning now to the figures, in one embodiment, a nerve fiber 110 asshown in FIG. 1A is accessed by an energy-emitting probe, for example,an RF ablation electrode 120 in the form of a needle as shown in FIG.1B. Upon application of energy to the electrode 120 a region of ablatedtissue 115, including ablated nerve fiber, may be formed as shown inFIG. 1C. Without further steps, nerve fiber will typically regeneratebetween axon ends 110 a, 110 b over a period of time, typically around 6to 18 months.

In accordance with the present disclosure, however, at least oneanti-regeneration agent may be introduced at the site at the time oftreatment (e.g., before, during and/or after ablation), thereby delayingor eliminating the need for a subsequent ablation treatment for thepatient. In certain instances, an anesthetic agent may also beintroduced to the treatment site to address any short term painassociated with the procedure.

In the particular embodiment shown, the electrode 120 employed in theRFA procedure is provided with an internal lumen (not shown) throughwhich an injectable composition containing one or more anti-regenerationagents 125 (also referred to herein as an “anti-regenerationcomposition”) can be delivered to the ablation site as shown in FIG. 1D.This is particularly desirable in that the ablation electrode 120 isalready positioned at the precise site of nerve destruction, and thusthe site where inhibition or prevention of nerve regeneration isdesired.

In certain embodiments, the needle electrode(s) employed may be, forinstance, small diameter (e.g., 16 gauge or smaller) and may include oneor more lumens through which the anti-regeneration composition may beinjected. The anti-regeneration composition may be injected, forexample, from at least one needle electrode 120 that contains an endopening or one or more side openings or, as illustrated in FIG. 2, bothan end opening 120 e and one or more side openings 120 s. The needleelectrode 120 may also contain an insulting sheath 122 to preventablation in regions other than at or near the electrode tip, as is knownin the art. In some embodiments, coolant may be introduced through theelectrode (i.e., in an open-irrigated RFA procedure) in order tomaintain lower tissue temperatures near the probe tip and allow largerlesion sizes to be achieved. Anti-regeneration agent may be introducedwith the coolant or as a separate injectable anti-regenerationcomposition. The holes may be round, oval, triangular, square, oressentially any other regular or irregular shape. Typical holedimensions may range, for example, from 0.002″ (0.05 mm) to 0.020″ (0.5mm) in width, among other possible values. In certain embodiments, theholes may be preferentially located radially around the needle to allowdirectionality in the introduction of injectable media.

Examples of injectable anti-regeneration compositions include solutionsthat contain one or more anti-regeneration agents, including higherviscosity solutions and gels (ranging, for example, up to 100,000 cp ormore, with the preferred value depending upon needle size, among othervariables). Other examples of injectable anti-regeneration compositionsinclude fluids that contain particles of the anti-regeneration agent,including higher viscosity particle dispersions and gels. The particlesin the particle-containing fluids may be in the form of, for example,(a) solid particles of anti-regeneration agent, (b) solid particlescomprising anti-regeneration agent dissolved or dispersed in a solidmatrix material, (c) encapsulated solid particles of anti-regenerationagent, (d) encapsulated particles comprising anti-regeneration agentdissolved or dispersed in a solid matrix material, and (e) encapsulatedsolutions, dispersions or gels comprising anti-regeneration agent.

Mechanisms for release of anti-regeneration agent from such particlesinclude bioerosion (e.g., due to particle dissolution, biodegradation,etc.), diffusion, or a combination of bioerosion and diffusion. Incertain embodiments, the encapsulation material may comprise ananesthetic for shorter term pain relief.

Examples of matrix materials and encapsulation materials include varioussynthetic biostable or biodegradable polymers, various naturallyoccurring polymers, as well as various biologics.

Examples of synthetic biostable polymers may be selected from thefollowing: (a) polyolefin homopolymers and copolymers, includinghomopolymers and copolymers of C2-C8 alkenes, for example, polyethyleneand polypropylene among others, (b) fluoropolymers, includinghomopolymers and copolymers of C2-C8 alkenes in which one or morehydrogen atoms are substituted with fluorine, for example,polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF),poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-HFP) among others,(c) polyamides such as nylons, among others, (d) polyesters, including,for example, polyethylene terephthalate, among others, (e) styreniccopolymers such as isobutylene-styrene copolymers, including blockcopolymers comprising one or more polystyrene blocks and one or morepolyisobutylene blocks, for instance,poly(styrene-b-isobutylene-b-styrene) (SIBS), among others, (e)polyurethanes such as polyisobutylene based polyurethanes (PIB-PU),among others, (f) as well as various other non-absorbable polymers suchas siloxanes or silicones.

Examples of synthetic biodegradable polymers may be selected, forexample, from polyesters and polyanhydrides, among others. Specificbiodegradable polymers may be selected from suitable members of thefollowing, among others: (a) polyester homopolymers and copolymers(including polyesters and poly[ester-amides]), such as polyglycolide,polylactide (PLA), including poly-L-lactide, poly-D-lactide, andpoly-D,L-lactide, poly(lactide-co-glycolide) (PLG), includingpoly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide) andpoly(D,L-lactide-co-glycolide), poly(beta-hydroxybutyrate),poly-D-gluconate, poly-L-gluconate, poly-D,L-gluconate,poly(epsilon-caprolactone), poly(delta-valerolactone),poly(p-dioxanone), poly(tri methylene carbonate),poly(lactide-co-delta-valerolactone),poly(lactide-co-epsilon-caprolactone), poly(lactide-co-beta-malic acid),poly(lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylenecarbonate), poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate),poly[1,3-bis(p-carboxyphenoxy)propane-co-sebacic acid], poly(sebacicacid-co-fumaric acid), and poly(ortho esters) such as those synthesizedby copolymerization of various diketene acetals and diols, among others;and (b) polyanhydride homopolymers and copolymers such as poly(adipicanhydride), poly(suberic anhydride), poly(sebacic anhydride),poly(dodecanedioic anhydride), poly(maleic anhydride),poly[1,3-bis(p-carboxyphenoxy)methane anhydride], andpoly[alpha,omega-bis(p-carboxyphenoxy)alkane anhydrides] such aspoly[1,3-bis(p-carboxyphenoxy)propane anhydride] andpoly[1,3-bis(p-carboxyphenoxy)hexane anhydride], among others.

Where copolymers are employed, copolymers with a variety of monomerratios may be available. For example, where PLG is used, a variety oflactide:glycolide molar ratios will find use herein, and the ratio islargely a matter of choice, depending in part on the rate of degradationdesired. For example, a 50:50 PLG polymer, containing 50% D,L-lactideand 50% glycolide, will provide a faster resorbing copolymer, while75:25 PLG degrades more slowly, and 85:15 and 90:10, even more slowly,due to the increased lactide component. Degradation rate can also becontrolled by such factors as polymer molecular weight and polymercrystallinity.

Examples of naturally occurring polymers include biostable andbiodegradable polymers such as cellulose, biocellulose, and alginates(non-crosslinked and ionically crosslinked).

As defined herein, a “biologic material” is a material that comprisesone or more extracellular matrix components. Biologic materials for useherein include crosslinked and non-crosslinked allograft (e.g., humancadaveric) materials, as well as crosslinked and non-crosslinkedheterograft (e.g., bovine, porcine, equine, etc.) materials. Specificexamples of non-crosslinked biologic materials include mammaliannon-crosslinked biologic matrix materials, such as human dermis, humanfascia lata, fetal bovine dermis and porcine small intestinal submucosa.Specific examples of crosslinked biologic materials include mammaliancrosslinked biologic materials such as crosslinked porcine dermis,crosslinked porcine small intestinal submucosa, crosslinked bovinepericardium, and crosslinked horse pericardium. Such materials aretypically acellular. Moreover, they are typically predominantlycollagen. Such biologic materials may be, for example, processed into aninjectable gelatinous material useful as a carrier for anti-regenerationagents. For example, small flat particles of such biologic materials maybe provided in conjunction with a suitable injection formulation. Uponinjection, such particles may form a physical barrier to nerve growth,without imposing an insurmountable barrier for agent release. In suchembodiments, particle size may be varied to change diffusion rates.

Examples of injectable anti-regeneration compositions for use hereininclude compositions that solidify in the body. For example, a hydrogelprecursor material that contains one or more anti-regeneration agents,for example, in dissolved or particle form, may be injected into thepatient. In some embodiments, a crosslinkable fluid formulation thatcontains one or more anti-regeneration agents, for example, in dissolvedor particle form, may be employed as an injectable anti-regenerationcomposition that solidifies in the body. The crosslinks that may beformed include covalent crosslinks hydrogen bonding crosslinks andphysical crosslinks or entanglements. Crosslinking may be promoted byresidual heat after ablation, high ion concentrations (e.g., from asaline cooling agent, where employed), additional low-level applied RFenergy and pH changes, among other mechanisms. In some embodiments, asolution containing one or more organic solvents, one or more dissolvedpolymers, and one or more anti-regeneration agents, for example, indissolved or particle form, may be employed as an injectableanti-regeneration composition that solidifies in the body. In theseembodiments, the dissolved polymer may precipitate as the organicsolvent(s) are absorbed by the body of the subject. Chemically sensitive(unstable) anti-regeneration agents may be encapsulated by biostable orbiodegradable polymers to protect them from solvents and chemicaldegradation from crosslinking reactions. In this manner the purity andchemical structure of anti-regeneration agent would be maintained.

It should be noted that where a solid or solidifiable composition isintroduced into a subject, the composition may provide a mechanicalbarrier to nerve regeneration alternatively or in addition to releasingan anti-regeneration agent, for example, by diffusion through porousmaterials and solid materials (e.g., where the anti-regeneration agentis a small molecule agent), among other mechanisms.

In various aspects of the present disclosure, ablation devices areprovided that have one or more components detachably connected to thedistal region of the device, which act to inhibit or prevent nerveregeneration upon being deposited in the body. Such devices may alsocontain a reservoir having the capacity to store and disperseanti-regeneration agents.

In some embodiments, for example, an ablation electrode may be providedwith a detachable anti-regeneration-agent-releasing sheath that can bedelivered to the ablation site for this purpose. As a specific example,a treatment device comprising a needle electrode 120 and insultingsheath 122 like that shown in FIG. 3A may be provided with an aleave-behind sheath 124 that covers the exposed distal end 120 d of theneedle electrode as shown in FIG. 3B. In the embodiment shown, thesheath 124 is provided with discrete holes 124 h that allow or enhancethe passage of current between the underlying needle electrode 120 andthe surrounding environment. Although the leave-behind sheath 124 shownhas discrete holes 124 h, in other embodiments, the leave-behind sheath124 may be of a micro-porous structure with hundreds, thousands,millions, or even more small pores through which current may pass.

In addition, the needle electrode 120 may include one or more lumensthrough which an additional anti-regeneration-agent-containingcomposition or an anesthetic-agent-containing composition may beinjected (see, e.g., FIG. 2). Alternatively or in addition, saline orother fluid may be injected through the one or more lumens, which maywet the leave-behind sheath to enhance energy transfer and/or to coolthe tip (in an open-irrigated manner).

In embodiments where a leave-behind sheath is provided, theanti-regeneration agent may be provided in a layer that is disposed overan underlying sheath material. For example, the layer may be a layer ofanti-regeneration agent per se, or the layer may be in the form of amatrix material within which the anti-regeneration agent is dissolved orwithin which particles of the anti-regeneration agent are dispersed. Ifdesired, an overlying layer may be provided in certain instances whichacts to slow release of the anti-regeneration agent and/or which maycomprise an anesthetic agent for shorter term pain relief.

Alternatively or in addition, an anti-regeneration agent may be providedwithin the sheath-forming material. For example, the sheath-formingmaterial may act as a matrix material within which the anti-regenerationagent is dissolved or within which particles of the anti-regenerationagent are dispersed. If desired, an overlying layer may be provided incertain instances which acts to slow release of the anti-regenerationagent and/or which comprises an anesthetic agent for shorter term painrelief.

Examples of matrix materials and materials for overlying layers includevarious synthetic biostable or biodegradable polymers, various naturallyoccurring polymers, as well as various biologics, such as those set forabove. As with the particulate forms described above, mechanisms forrelease of anti-regeneration agent include bioerosion (e.g., due toparticle dissolution, biodegradation, etc.), diffusion, or a combinationof bioerosion and diffusion.

After treatment with the needle electrode 120 has been completed, theneedle electrode 120 is removed and the sheath 124 is left behind forlong-term delivery of anti-regeneration agent and, optionally, shortterm delivery of anesthetic agent. In some embodiments, the leave-behindsheath 124 may be detachably secured over the needle electrode 120 suchthat the sheath 124 slips off of the needle electrode 120 when it isretracted from the treatment site. In other embodiments, the insultingsheath 122 may be configured such that it can be advanced relative tothe needle electrode 120, such that the leave-behind sheath 124 ispushed from the distal tip of the needle electrode 120. In still otherembodiments, the position of the needle electrode 120 and insulatingsheath 122 may remain fixed, and a separate sheath 126 (see, e.g., FIG.3C) may be advanced over the insulating sheath 122 and engage theleave-behind sheath 124, thereby pushing the leave-behind sheath 124from the distal tip of the needle electrode 120.

In certain embodiments, the leave-behind sheath 124 may crumple whenpushed from the distal tip of the needle electrode 120 as shown in FIG.3D. In other embodiments, the sheath 124 may substantially retain itsshape when pushed from the distal tip of the needle electrode 120,thereby maintaining its inner lumen to serve additional functions suchas those described below.

One specific example of the steps that may be employed in the use of aleave-behind sheath follows: (a) insert device to target location, (b)confirm placement via an appropriate method (e.g. fluoroscopic,ultrasound, stimulation, etc.), (c) deliver therapeutic energy (e.g.radiofrequency energy), (d) push the insulative sheath while pulling theconductive element associated with the electrode, causing theleave-behind sheath to be pushed beyond the distal tip of the needleelectrode, (e) if necessary, twist the insulative sheath gently tofinish detachment from the leave-behind sheath, and (f) removeinsulative sheath and conductive element.

In certain embodiments, the leave-behind sheath may be provided with alumen that can be attached to a vacuum source for suction, allowing anerve ending to be drawn into the sheath subsequent to ablation, therebypreventing the nerve ending from rejoining with another.

In certain embodiments, an electromagnetic source, a chemical attractantsuch as an agent that provides an electrochemical “pulse,” and/oranother agent that attracts generation of previously ablated nerve maybe associated with the leave-behind sheath (e.g., placed within theleave-behind sheath lumen), causing the nerve to grow into the sheathlumen and terminate, thus preventing the axon ends fromre-attaching/growing back together. For example, one or more chemicals,such as those naturally present in the body that contribute to nerveregeneration, may be disposed inside the conduit to attract the nerveand cause the nerve to grow into the conduit. As another example,electromagnetic pulses, at specific frequencies and burst patterns, maybe generated to attract nerve ends into the conduit. In some instances,the specific frequencies and burst patterns employed may be based on theparticular nerve being targeted, as each peripheral nerve may havedifferent intrinsic action potential firing rates. Electromagneticpulses may be applied, for example, via a conventional or miniatureimplantable pulse generator (IPG) associated with the conduit and/or viainductive coupling to provide energy via an external signal generator.The frequency of pulses and/or bursts of pulses may range, for example,between 1 and 100 Hertz, among other values. Electromagnetic sources mayfurther include light sources, for example, LED light sources, amongothers, which may be placed inside the conduit to attract the nerveending to regenerate into the conduit. In some cases, the conduit mayhave only one entrance. In some cases, the conduit may contain one ormore anti-regeneration agents such as those described above, to preventthe nerve from growing further.

Alternatively, the nerve may be captured within a lumen of a sheath(e.g., by suction), where it may be, for example, treated with asuitable energy source or sink (e.g., RF energy, laser, ultrasound,cryogenic treatment, etc.), mechanically cut, or chemically ablated(e.g., using ethanol or another chemical agent). Subsequently, the endsmay optionally be capped, for example, by injecting a crosslinkablepolymer formulation into the sheath. After treatment, the sheath may beleft behind, for example, using one of the approaches described above.

In other aspects of the present disclosure, anti-regeneration agent maybe released at a site of ablation by filling a reservoir by injection invivo and subsequently allowing the anti-regeneration agent to bereleased from the reservoir.

For example, and with reference to FIG. 4, a deflated and detachableballoon reservoir 424 may be inserted into a site adjacent a nerve 410to be treated (for example, using a suitable imaging modality such asx-ray or ultrasound imaging, among other possibilities). The balloonreservoir 424 is connected to a catheter 429 that can be removed at theend of the procedure. The reservoir 424 may be inflated through a lumenof the catheter 429, which inflation can cause a mechanical compressioneffect on the nerve 410. The inflation medium may be, for example,saline, or may contain one or more anti-regeneration agents such asthose described elsewhere herein (e.g., myelin associated glycoprotein(MAG), oligodendrocyte-myelin glycoprotein (OMpg), chondroitin sulfateproteoglycans, etc.), allowing the reservoir to be filled withanti-regeneration agent. The reservoir may be provided, for example,with a one-way valve to prevent escape of the inflation fluid along theroute by which it is introduced. The one or more anti-nerve regenerationsubstances are subsequently slowly released from the reservoir 424 forexample, by diffusion through the reservoir wall or by seeping out ofpores that are formed in the reservoir wall, among other possiblemechanisms.

The reservoir may also be provided with electrodes 420 for RF ablation.For instance, RF ablation may be conducted at the time of inflation bysupplying energy to the electrodes 420 via a catheter 429 in the form ofa hollow conductor (which may be provided with an insulative coating asdescribed above). In certain embodiments, the electrodes 420 may beenergized wirelessly, circumventing the need for a conductor-containingcatheter 429.

In certain embodiments, a catheter 429 may be inserted at a later datefor re-inflation of the reservoir 424 and/or to conduct additionalablation procedures. The reservoir 424 may further be provided with asuitable marking structure (e.g., a structure visible under ultrasound,fluoroscopy, etc.) to locate the reservoir 424 for future insertions,ablations and inflations. In certain embodiments, the reservoir 424 maybe removed by deflating the reservoir 424 after a predetermined periodof time.

In a related embodiment, and with reference to FIG. 5, an electrode(e.g., a hollow needle-shaped electrode structure 520) may be introducedinto a treatment site, while inserted into a tubular shaft 528associated with a balloon-like structure 524, at which point an ablationprocedure is performed using the electrode structure 520. Subsequently,the balloon may be inflated with a suitable inflation fluid, forexample, saline or a fluid containing one or more anti-regenerationagents as described above. The balloon 524 may be further provided withbarbs 527 to secure the balloon 524 to surrounding tissue. Where formedof a conductive material and in electrical communication with aninserted conductor, the barbs 527 may also function as electrodes for RFablation. After inflation, electrode structure 520 may be removed,leaving the balloon 524 and shaft 528 in the patient. The shaft 528 mayfurther be provided with a magnetic ring 529 or other suitable markingstructure (e.g., a structure visible under ultrasound, fluoroscopy,etc.) to locate the structure for future insertions, ablations andinflations. In certain embodiments, the balloon 524 and tubular shaft528 may be left behind just under the skin surface.

In other aspects of the present disclosure, a device may be providedwhich is clamped around a nerve fiber, severing the nerve fiber, andwhich may also create an anti-regeneration-agent-containing environmentaround the severed nerve ends. For example, referring now to FIG. 6, adevice 621 is shown, which includes two hinged semi-cylindrical pieces621 a, 621 b, which have been closed around a nerve fiber 610. Thedevice further includes at least one cutting member, specifically,blades 623 a, 623 b that meet and sever the nerve fiber 610, when thesemi-cylindrical pieces 621 a, 621 b are snapped shut around the nervefiber. The cutting member may then act as a barrier to nerveregeneration. Alternatively or in addition, the device 621 may furtherbe provided with at least one anti-regeneration agent. For example, thesemi-cylindrical pieces 621 a, 621 b may contain and elute ananti-regeneration agent, or an anti-regeneration-agent-containingcomposition, for instance, in the form of ananti-regeneration-agent-containing liquid, gel or solid, may be includedin the interior of the device.

As previously suggested, an additional potential feature of any solidmaterial described herein that is implanted in the patient (e.g.,compositions that solidify in the body, leave-behind sheath, inflatablereservoir, cutting device) may be provided with a suitable imagingcontrast agent that serves as a “marker” for subsequent proceduresshould they be needed. Examples of imaging contrast agents include, forexample, (a) contrast agents for use in connection with x-rayfluoroscopy, including metals, metal salts and oxides (particularlybismuth salts and oxides), and iodinated compounds, among others, (b)contrast agents for use in conjunction with ultrasound imaging,including inorganic and organic echogenic particles (i.e., particlesthat result in an increase in the reflected ultrasonic energy) orinorganic and organic echolucent particles (i.e., particles that resultin a decrease in the reflected ultrasonic energy), and (c) contrastagents for use in conjunction with magnetic resonance imaging (MRI),including contrast agents that contain elements with relatively largemagnetic moment such as Gd(III), Mn(II), Fe(III).

While the devices and methods of this disclosure have been described interms of various preferred embodiments, it may be apparent to those ofskill in the art that variations can be applied without departing fromthe concept, spirit and scope of the disclosure. All such similarsubstitutes and modifications apparent to those skilled in the art aredeemed to be within the spirit, scope and concept of the disclosure asdefined by the appended claims.

The invention claimed is:
 1. A method of treatment comprisingdenervating a nerve fiber using a radiofrequency ablation (RFA)procedure at a target site in a subject; introducing at least oneanti-regeneration chemical agent that inhibits or prevents nerveregeneration to the target site, wherein the chemical agent is one of:an anti-microtubule agent, an anti-neoplastic agent, a glial scarformation agent, an agent to induce the collapse or paralysis ofneuronal growth cones, or a chemical agent that de-activates Schwanncells; introducing a solid, detachable sheath at the target site that ispositioned at a distal end of a medical device, wherein a material ofthe detachable sheath comprises a growth agent that causes an ablatednerve to grow into the detachable sheath; and optionally introducing oneor more anesthetic agents to the target site.
 2. The method of treatmentof claim 1, wherein the chemical agent is introduced to the target siteas an injectable composition.
 3. The method of treatment of claim 1,wherein the chemical agent is introduced to the target site by filling areservoir by injection in vivo.
 4. The method of treatment of claim 1,wherein a device that contains the chemical agent is clamped around asevered nerve and wherein the device exposes the severed nerve to thechemical agent.
 5. The method of treatment of claim 1, wherein thesolid, detachable sheath comprises a chemical agent that inhibits orprevents nerve regeneration.
 6. The method of treatment of claim 1,wherein a fluid is introduced to the target site and the fluidsolidifies at the target site to form the solid, detachable sheath. 7.The method of treatment of claim 1, wherein the medical device comprisesan ablation electrode and the detachable sheath is disposed over theablation electrode.
 8. The method of treatment of claim 1, wherein themedical device comprises a lumen through which a vacuum source isapplied to the detachable sheath.
 9. The method of treatment of claim 1,wherein the chemical agent is one of: a taxol, vincristine, vindesine,vinorelbine, Nocodazole, Myelin-Associated Glycoprotein (MAG), orSemaphorin-3A.
 10. A method of treatment comprising (a) conducting adenervation procedure at a target site in a subject, (b) introducing atleast one anti-regeneration agent that inhibits or prevents nerveregeneration to the target site, and (c) optionally introducing one ormore anesthetic agents to the target site; wherein a solid material isintroduced to the target site or is formed at the target site, whereinthe solid material is a detachable material that is positioned at adistal end of a medical device comprising a detachable sheath, whereinthe detachable sheath comprises an agent that causes an ablated nerve togrow into the detachable sheath.
 11. The method of claim 10 wherein thedenervation procedure is a radiofrequency ablation (RFA) procedure. 12.The method of claim 10 wherein the step of conducting a denervationprocedure at a target site in a subject comprises using a medical devicethat applies energy to a target site in a subject; wherein the at leastone anti-regeneration agent is one of: an anti-microtubule agent, ananti-neoplastic agent, a glial scar formation agent, an agent to inducethe collapse or paralysis of neuronal growth cones, or a chemical agentthat de-activates Schwann cells.
 13. The method of claim 12, wherein theenergy applied is a radiofrequency energy, laser energy, ultrasoundenergy, microwave energy, or cryogenic energy.
 14. The method of claim12, wherein the target site includes a facet joint, a sacroiliac joint,a knee, a foot, or a hip.
 15. The method of claim 12, wherein thedisease or condition includes at least one of chronic pain,hypertension, pulmonary arterial hypertension, asthma, chronicobstructive pulmonary disease, diabetes, metabolic syndrome, heartfailure, arrhythmias, chronic kidney disease, obstructive sleep apnea,and overactive bladder syndrome.